Neuronal replacement strategies using stem cells or fetal transplants are potential treatments for neurological disorders caused by damage or degeneration of specific neural circuits in the central nervous system (CNS). Parkinson's disease (PD) is one such disorder, caused by the degeneration of dopaminergic neurons in the substantia nigra. Many investigators have already explored neural transplantation as therapy for PD, both in the lab and in the clinic, but in most cases, dopaminergic neurons are transplanted directly into their target - the striatum - rather than into their site of origin, the substantia nigra (SN). This leads to incomplete recovery of function both in animal models and in human PD patients, because the transplanted neurons provide a dopamine source to the striatum but do not reestablish the degenerated neural circuit. This proposal shall examine the hypothesis that a growth-supportive pathway created between the SN and the striatum can guide the growth of axons from dopaminergic neurons transplanted into the SN of the parkinsonian brain, resulting in an anatomically and physiologically correct reestablishment of the nigrostriatal pathway and an amelioration of parkinsonian symptoms. Preliminary data is presented showing that a combination of glial cell line-derived neurotrophic factor (GDNF) and its alpha-1co-receptor (GFR-11) or netrin-1 support long distance axon growth from dopaminergic transplants in the SN to the striatum. In this study, a series of experiments are proposed to further enhance the growth along the pathway and targeting within the striatum. The specific aims are to: 1) examine these and other potential growth factor candidates either individually and in combination for their ability to support long distance growth of dopaminergic axons within the adult brain; 2) examine the ability BDNF and chondroitinase to enhance axon branching and synaptogenesis within the adult striatum; 3) reconstruct the nigrostriatal pathway using data acquired from Aims 1 and 2 and examine functional recovery; 4) examine the release of dopamine, cell type specificity (A9/A10 neurons), and synaptic connectivity of dopaminergic axons re-innervating the striatum. The outcome of these studies will demonstrate the feasibility of targeting the growth of axons using neuronal replacement to ameliorate the symptoms of Parkinson's disease. These studies will also provide a model for developing neuronal replacement strategies for other neurological disorders. PUBLIC HEALTH RELEVANCE Parkinson's disease is a widespread neurodegenerative disease that manifests severe motor dysfunction ultimately leading to death. Present cell replacement therapies and drug treatments have either failed in clinical trials or induce long term side effect and loss of efficacy over time. Neuronal replacement strategies that rebuild the damage circuit have a high probability of reducing or reversing motor deficits associated with Parkinson's disease as well as numerous other neurological disorders.